Understanding Your Treatment Options Mast Cell Activation Syndrome (MCAS) A Client Guide to Current and Emerging Therapies

Prepared by Yoon Hang Kim, MD, MPH

www.directintegrativecare.com

What Is MCAS?

Mast Cell Activation Syndrome (MCAS) occurs when mast cells—immune cells found throughout your body—release their chemical messengers (mediators) too easily or too often. This can cause a wide range of symptoms affecting the skin, gut, heart, lungs, and nervous system. Treatment follows a stepwise approach, starting with medications that block or reduce these mediator effects and escalating to more targeted therapies when needed.

Step 1: Foundation Therapies (Antimediator Treatment)

Before considering advanced options, we work to maximize the benefit of foundational medications. These form the backbone of MCAS management and are recommended by both the American Academy of Allergy, Asthma & Immunology (AAAAI) and the National Comprehensive Cancer Network (NCCN):

• H1 antihistamines (e.g., cetirizine, loratadine, fexofenadine)—can be dosed up to four times the standard dose under medical supervision
• H2 antihistamines (e.g., famotidine)—help with GI symptoms and work synergistically with H1 blockers
• Leukotriene receptor antagonists (e.g., montelukast)—helpful for respiratory and inflammatory symptoms
• Cromolyn sodium—a mast cell stabilizer, especially useful for GI-predominant symptoms
• Ketotifen—a mast cell stabilizer with antihistamine properties
• Aspirin—in selected clients, helps block prostaglandin-mediated flushing and pain
• Short courses of corticosteroids—reserved for acute flares that do not respond to the above

When these therapies are insufficient to control symptoms, we consider the advanced options described below.

Step 2: Omalizumab (Xolair)—Anti-IgE Biologic

Omalizumab is the most well-studied biologic for MCAS that does not respond to standard antimediator therapy. It works by binding IgE—a key trigger for mast cell activation—thereby reducing the frequency and severity of mast cell degranulation.

What the research shows: In a systematic review of clients with refractory MCAS, roughly 61% experienced a partial response and 18% achieved a complete response, with higher doses generally associated with better outcomes. A separate study of 55 clients with various mast cell disorders reported an overall response rate of approximately 78%, with particularly notable improvements in flushing, blood pressure instability, and gastrointestinal symptoms. In clients with idiopathic MCAS specifically, omalizumab significantly reduced the number of anaphylaxis episodes and overall symptom severity over 6–12 months.

How it is given: Omalizumab is an injection given every 2–4 weeks. Dosing typically ranges from 150 mg to 300 mg per month, though some clients require higher doses (up to 600 mg). It is used off-label for MCAS—meaning it is not FDA-approved specifically for this condition, but there is growing clinical evidence and experience supporting its use.

When Clonal Mast Cell Disease Is Present: Targeted Therapies

If testing reveals a clonal mast cell population (such as a KIT D816V mutation), additional targeted therapies may be appropriate. These are more commonly used in systemic mastocytosis but may be relevant for some MCAS clients.

Avapritinib (Ayvakit) is a selective inhibitor of the KIT D816V mutation—the most common genetic driver of abnormal mast cell growth. It is FDA-approved for both advanced and indolent systemic mastocytosis. In addition to reducing mast cell burden, it also appears to reduce IgE-triggered degranulation. The NCCN guidelines list avapritinib as the preferred treatment for symptomatic indolent systemic mastocytosis that has not responded to antimediator therapy.

Midostaurin (Rydapt) is a multikinase inhibitor FDA-approved for advanced systemic mastocytosis. In small studies, it resolved anaphylactic episodes in 75–100% of clients with advanced disease. It may be considered when avapritinib is not effective or not tolerated.

Emerging and Investigational Therapies

Several newer medications are showing promise for mast cell-driven conditions and may become relevant treatment options in the near future:

Dupilumab (Dupixent) blocks the IL-4 receptor alpha, a key player in type 2 (allergic) inflammation. It is FDA-approved for several allergic conditions and has recently been approved for chronic spontaneous urticaria (CSU). It may benefit MCAS clients who have overlapping allergic or type 2 inflammatory features.

Remibrutinib (Rhapsido) is an oral BTK (Bruton’s tyrosine kinase) inhibitor recently FDA-approved for antihistamine-refractory chronic spontaneous urticaria. BTK sits downstream of the IgE receptor on mast cells, and blocking it reduces mast cell signaling. This class of medication is a promising new avenue for mast cell-driven disease.

Barzolvolimab (investigational) is an anti-KIT monoclonal antibody that directly depletes mast cells. Early clinical trials in chronic urticaria have shown robust and sustained symptom reduction. It is not yet FDA-approved.

Lirentelimab (investigational) targets Siglec-8, a receptor found on mast cells and eosinophils. Early results in indolent systemic mastocytosis were promising, though broader clinical development has had mixed outcomes. Research is ongoing.

Key Takeaways

• MCAS treatment is stepwise—we start with the foundation and escalate thoughtfully based on your response.
• Omalizumab is currently the best-supported biologic option for refractory MCAS.
• If a clonal mast cell population is identified, targeted therapies like avapritinib may offer significant benefit.
• Several exciting new medications are in development or newly approved for related conditions, and may expand treatment options in the coming years.
• Every treatment plan is individualized. We will work together to find the approach that best manages your symptoms while considering safety, cost, and quality of life.

If you have questions about any of these options or want to discuss whether a particular therapy may be right for you, please bring this handout to your next appointment or reach out to us at Direct Integrative Care.

About Dr. Kim

Yoon Hang Kim, MD, MPH

Board-Certified in Preventive Medicine | Integrative & Functional Medicine Physician

Dr. Kim is a board-certified Preventive Medicine physician with over 20 years of experience in integrative and functional medicine. He completed his fellowship at the University of Arizona Andrew Weil Center for Integrative Medicine and holds certifications in preventive medicine, medical acupuncture, and integrative/holistic medicine. He specializes in low dose naltrexone (LDN), autoimmune conditions, chronic pain, integrative oncology, fibromyalgia, chronic fatigue syndrome, mast cell activation syndrome, and mold toxicity. He is the author of three books and over 20 peer-reviewed articles.

Professional: www.yoonhangkim.com  |  Clinical: www.directintegrativecare.com